Techniques recently developed in this laboratory have made it possible to define precisely the genetic composition of influenza A virus recombinants with respect to the derivation of each of the 8 genes and their respective gene products. This application proposes to analyze parent viruses, and genetically defined recombinants with respect to the kinetics of their replication in embryonated eggs and in three different cell culture systems as well as their virulence in mice following aerosol infection. By examination of recombinants which differ from parent viruses or from each other with respect to the derivation of a single gene it should be possible to determine which genes contribute to strain related differences in biological behavior in these systems. Although such analysis will not provide evidence directly related to strain associated differences in virulence in man, by disclosing which gene products contribute to adaptation to different hosts the results may enhance our understanding of the process of attenuation, and hence facilitate the production of live virus vaccines.